Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro and in vivo to elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells.

Children's Cancer Institute Lowy Cancer Research Centre UNSW Sydney Randwick NSW Australia; School of Biomedical Sciences UNSW Sydney Randwick NSW Australia

Department of Experimental Oncology IEO IRCCS Istituto Europeo di Oncologia Milan Italy

Department of Experimental Oncology IEO IRCCS Istituto Europeo di Oncologia Milan Italy; Department of Oncology and Hemato Oncology Università degli Studi di Milano Milan Italy

IFOM Milan Italy; Department of Oncology and Hemato Oncology Università degli Studi di Milano Milan Italy

Institute for Clinical Chemistry and Laboratory Medicine University Hospital and Faculty of Medicine Technische Universität Dresden Dresden Germany; Medical Clinic 1 University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

Institute for Clinical Chemistry and Laboratory Medicine University Hospital and Faculty of Medicine Technische Universität Dresden Dresden Germany; Medical Clinic 1 University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany; Mildred Scheel Early Career Center National Center for Tumor Diseases Dresden University Hospital and Faculty of Medicine Technische Universität Dresden Dresden Germany

Institute for Clinical Chemistry and Laboratory Medicine University Hospital and Faculty of Medicine Technische Universität Dresden Dresden Germany; Medical Clinic 1 University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany; Mildred Scheel Early Career Center National Center for Tumor Diseases Dresden University Hospital and Faculty of Medicine Technische Universität Dresden Dresden Germany; Laboratory of Cancer Cell Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Turku Bioscience Centre University of Turku and Åbo Akademi University Turku Finland; Institute of Biomedicine University of Turku Turku Finland

Citace poskytuje Crossref.org